Periodic Reporting for period 1 - EPiTB (EPiTB: Addressing an unmet need: same day diagnosis of extra-pulmonary TB in a high burden setting.)
Reporting period: 2023-05-01 to 2024-10-31
Tuberculosis (TB) remains one of the leading causes of death in the developing world, particularly in Africa, where the fight against the disease faces significant challenges. Extrapulmonary TB (EPTB), a form of the disease affecting areas outside the lungs, accounts for 15-20% of the 11 million newly diagnosed TB cases in the world each year. In regions with high rates of HIV, EPTB accounts for over 30% of TB cases, yet current diagnostic tools fall short in detecting EPTB. Most diagnostic tests for TB are designed to detect the presence of M.tb bacilli in a sample, such as the current first-line GeneXpert test, or TB culture. These tests perform exceptionally well in sputum samples, where the bacterial load is relatively high, however, in EPTB, patients rarely produce sputum and the fluid collections (serosal effusions) in the pleural, pericardial, and peritoneal space, as well as in CSF, are paucibacillary. There is therefore a critical gap in diagnostic capabilities for EPTB, as the assays designed to detect mycobacterial DNA perform poorly in samples with low bacterial load. These samples are the result of an immune-mediated response and thus, a test is required that can identify this response. This test must be highly sensitive and highly specific in order to address the unmet need of EPTB diagnosis.
In the absence of reliable diagnostic tests, clinicians are left with no alternative but to initiate empiric TB treatment in patients with suggestive clinical signs and symptoms. This increases morbidity, as patients are exposed to unnecessary TB treatment, and furthermore, the diagnosis of other potentially life-threatening conditions, such as cancer, is delayed. Clinicians currently use a cluster of tests, including Gene Xpert, TB culture, and adenosine deaminase (ADA; an enzyme that accumulates in high concentrations in extra-pulmonary fluid when host T-cells are stimulated by TB antigen, however, conditions such as empyema, lymphoma, other infections, and malignancies can also induce a raised ADA levels), however, the lack of sensitivity of GeneXpert and TB culture in serosal fluid and the poor specificity of ADA make empiric treatment the only option in many cases. The reference standard for the diagnosis of tuberculous pleural effusion is through pleural biopsy, however this procedure is inaccessible to many patients in the developing world due to a lack of skilled pulmonologists and physicians, as well as a lack of equipment to perform the procedure.
The Epi-TB project seeks to address the unmet need within EPTB diagnosis through a groundbreaking diagnostic tool, IRISA-TB, developed by Antrum Biotech, a University of Cape Town spin-off. IRISA-TB offers a low-cost, same-day diagnostic solution that has already shown promise in smaller clinical trials. Interferon-gamma is a well-established, specific biomarker used in the diagnosis of tuberculosis. Traditionally used to detect latent TB infection by stimulating blood samples with TB antigen and observing the release of interferon-gamma in the sample, the Epi-TB project is evaluating an interferon-gamma detection assay for the diagnosis of active TB when used in EPTB fluid samples.
This large-scale study will evaluate IRISA-TB in various types of EPTB across South Africa, Zambia, and Zimbabwe, with the goal of improving TB diagnosis and treatment in real-world settings.
The Epi-TB study consists of two scientific projects:
1. A prospective cohort study aiming to recruit 2160 participants with suspected extrapulmonary TB (pleural, pericardial, peritoneal, or TB meningitis) with a nested health economics study to evaluate the cost implications of various diagnostic strategies.
2. A laboratory-based study which aims to develop a point-of-care assay based on the IRISA-TB test. This will take the diagnosis of extrapulmonary TB from the laboratory to the patient's bedside.
We anticipate that the project will have a direct impact on participants’ pathways to diagnosis and their clinical outcomes through rapid diagnosis or exclusion of extrapulmonary TB. The project has excellent engagement with policy-makers and end users at all the recruitment sites and there is an excellent opportunity for uptake of the IRISA-TB assay into national TB programmes in the participating countries. IRISA-TB is a highly sensitive and specific test that enables same-day diagnosis of EPTB.
The project is aiming to extend its impact beyond the scope of the Epi-TB clinical trial through the development of a point-of-care assay that performs as well as the current lab-based IRISA-TB test. Such a test will enable minimally trained staff to diagnose extrapulmonary TB at the bedside, allowing for rapid treatment initiation or referral, reduced empiric treatment rates, reduced pre-treatment loss to follow up and an overall reduction in morbidity and mortality. By promoting an African-designed innovation, Epi-TB aims to revolutionize TB diagnosis and support the fight against this deadly disease.
In the absence of reliable diagnostic tests, clinicians are left with no alternative but to initiate empiric TB treatment in patients with suggestive clinical signs and symptoms. This increases morbidity, as patients are exposed to unnecessary TB treatment, and furthermore, the diagnosis of other potentially life-threatening conditions, such as cancer, is delayed. Clinicians currently use a cluster of tests, including Gene Xpert, TB culture, and adenosine deaminase (ADA; an enzyme that accumulates in high concentrations in extra-pulmonary fluid when host T-cells are stimulated by TB antigen, however, conditions such as empyema, lymphoma, other infections, and malignancies can also induce a raised ADA levels), however, the lack of sensitivity of GeneXpert and TB culture in serosal fluid and the poor specificity of ADA make empiric treatment the only option in many cases. The reference standard for the diagnosis of tuberculous pleural effusion is through pleural biopsy, however this procedure is inaccessible to many patients in the developing world due to a lack of skilled pulmonologists and physicians, as well as a lack of equipment to perform the procedure.
The Epi-TB project seeks to address the unmet need within EPTB diagnosis through a groundbreaking diagnostic tool, IRISA-TB, developed by Antrum Biotech, a University of Cape Town spin-off. IRISA-TB offers a low-cost, same-day diagnostic solution that has already shown promise in smaller clinical trials. Interferon-gamma is a well-established, specific biomarker used in the diagnosis of tuberculosis. Traditionally used to detect latent TB infection by stimulating blood samples with TB antigen and observing the release of interferon-gamma in the sample, the Epi-TB project is evaluating an interferon-gamma detection assay for the diagnosis of active TB when used in EPTB fluid samples.
This large-scale study will evaluate IRISA-TB in various types of EPTB across South Africa, Zambia, and Zimbabwe, with the goal of improving TB diagnosis and treatment in real-world settings.
The Epi-TB study consists of two scientific projects:
1. A prospective cohort study aiming to recruit 2160 participants with suspected extrapulmonary TB (pleural, pericardial, peritoneal, or TB meningitis) with a nested health economics study to evaluate the cost implications of various diagnostic strategies.
2. A laboratory-based study which aims to develop a point-of-care assay based on the IRISA-TB test. This will take the diagnosis of extrapulmonary TB from the laboratory to the patient's bedside.
We anticipate that the project will have a direct impact on participants’ pathways to diagnosis and their clinical outcomes through rapid diagnosis or exclusion of extrapulmonary TB. The project has excellent engagement with policy-makers and end users at all the recruitment sites and there is an excellent opportunity for uptake of the IRISA-TB assay into national TB programmes in the participating countries. IRISA-TB is a highly sensitive and specific test that enables same-day diagnosis of EPTB.
The project is aiming to extend its impact beyond the scope of the Epi-TB clinical trial through the development of a point-of-care assay that performs as well as the current lab-based IRISA-TB test. Such a test will enable minimally trained staff to diagnose extrapulmonary TB at the bedside, allowing for rapid treatment initiation or referral, reduced empiric treatment rates, reduced pre-treatment loss to follow up and an overall reduction in morbidity and mortality. By promoting an African-designed innovation, Epi-TB aims to revolutionize TB diagnosis and support the fight against this deadly disease.
As of December 2024, the project has recruited 25% percent of its envisioned cohort. Recruitment is ongoing and interim results will be available within the coming months. The study has built positive collaborative relationships with clinicians, fellow researchers, and local health authorities at all recruitment sites and has contributed to capacity development in the form of clinical equipment, training of clinical staff, and supporting postgraduate research projects.
Clinicians have shown a keen interest and high uptake of the IRISA-TB assay’s results. Preliminary data suggests that IRISA-TB is performing well, particularly in its role as a ‘rule-out’ test.
The team at Leiden University Medical Centre have had very promising results with the development of a point-of-care assay. Preliminary data suggest a limit of detection similar to the laboratory-based version of IRISA-TB in pleural fluid samples. The next phase of the project will see this work being performed on all the different sample cohorts – pericardial, peritoneal, and cerebrospinal fluid, with the goal of developing a prototype by the end of the project. This prototype will then undergo validation using biobanked samples from the Epi-TB study and finally validation will be done on prospectively collected samples as part of a future project.
Results from the interim analysis in mid-2025 will be published here once available.
Clinicians have shown a keen interest and high uptake of the IRISA-TB assay’s results. Preliminary data suggests that IRISA-TB is performing well, particularly in its role as a ‘rule-out’ test.
The team at Leiden University Medical Centre have had very promising results with the development of a point-of-care assay. Preliminary data suggest a limit of detection similar to the laboratory-based version of IRISA-TB in pleural fluid samples. The next phase of the project will see this work being performed on all the different sample cohorts – pericardial, peritoneal, and cerebrospinal fluid, with the goal of developing a prototype by the end of the project. This prototype will then undergo validation using biobanked samples from the Epi-TB study and finally validation will be done on prospectively collected samples as part of a future project.
Results from the interim analysis in mid-2025 will be published here once available.
There are no published results available for the Epi-TB project at this stage. Preliminary results will be shared once we have reached 50% recruitment. From the participants recruited thus far, a TB positivity rate of around 25% has been observed, with an even greater proportion of participants testing IRISA-TB positive. The performance of the IRISA-TB test thus far shows great promise for its role in identifying extrapulmonary TB and reducing empiric TB treatment rates. Preliminary data show that the limit of detection for the point-of-care assay is comparable to that of IRISA-TB.